MOLECULAR DYNAMICS STUDIES OF GATING MECHANISM OF MSCL AS A FUNCTION OF HELIX T

MSCL门控机制作为螺旋T函数的分子动力学研究

• 批准号: 7956256
• 负责人: Wonpil Im
• 金额: $ 0.08万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956256
• 关键词: Binding; Biomedical Research; C-terminal; Complex; Computer Retrieval of Information on Scientific Projects Database; Cytoplasm; Funding; Grant; High Performance Computing; Homo; Image; Institution; Lipid Bilayers; Lipids; Membrane; Research; Research Personnel; Resources; Shapes; Side; Source; Structure; Surface Tension; System; Temperature; Transmembrane Domain; United States National Institutes of Health; molecular dynamics; periplasm; pressure; restraint; simulation; web site

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. MscL, the mechanosensitive channel of large conductance, forms a homo-pentameric pore in which each subunit contains two transmembrane (TM) domains (TM1 and TM2) involved in the channel gating, and a C-terminal cytoplasmic helical domain. The crystal structure (PDB ID:2OAR) represents a closed state of the channel, showing a funnel shaped pore with a large opening on the periplasmic side and the narrowest point near the cytoplasm. Assuming that TM helix tilting due to membrane tension drives MscL gating, we will perform molecular dynamics simulations by applying the recently developed helix tilt restraint potential to the TM helices of MscL in a DMPC lipid bilayer. An initial structure of the MscL/DMPC complex without C-terminal helix (Gln110-Asn125) was generated using Membrane Builder in the CHARMM-GUI website (http://www.charmm-gui.org). CT?P (constant temperature, surface tension, and pressure) dynamics will be used to allow the system size along the XY axes to vary during the simulation. The P21 image transformation will be used to allow the number of lipid molecules in the top and bottom leaflets to vary during the simulations. Three different simulations will be performed by tilting (1) both TM1 and TM2 helices (10 restraints), (2) only TM1 helices (5 restraints), and (3) only TM2 helices (5 restraints). The tilt angles of TM1 helices will be gradually varied from 35 (PDB ID:2OAR) to 65 by 1 and those of TM2 from 33 (PDB ID:2OAR) to 63 by 1, together or separately. We will analyze the change of the pore size, molecular interactions, and pressure profile as a function of helix tilt to explore the possible gating mechanisms of MscL at the atomic level.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 MSCL是大电导率的机械敏感通道，形成了一个同型孔孔，其中每个亚基包含两个参与通道门控的跨膜（TM）域（TM1和TM2），以及一个C末端的细胞质螺旋域。晶体结构（PDB ID：2OAR）代表通道的封闭状态，显示了漏斗形的孔，周围的侧面有较大的开口，并且靠近细胞质的孔。假设由于膜张力引起的TM螺旋倾斜驱动MSCL门控，我们将通过将最近开发的Helix TILT约束电位应用于MSCL的TM螺旋螺旋中的DMPC脂质双层。在Charmm-GUI网站（http://www.charmm-gui.org）中，使用膜构建器生成了没有C末端螺旋的MSCL/DMPC复合物（GLN110-ASN125）的初始结构。 CT？P（恒温，表面张力和压力）动力学将用于允许沿XY轴的系统尺寸在模拟过程中变化。 p21图像转化将用于允许在模拟过程中允许顶部和底部小叶中的脂质分子数量变化。通过倾斜（1）TM1和TM2螺旋（10个约束），（2）仅TM1螺旋（5个约束），以及（3）仅TM2螺旋（5个约束），将进行三个不同的模拟。 TM1螺旋的倾斜角将逐渐从35（PDB ID：2OAR）变化到65 x 1，而TM2的倾斜角度从33（PDB ID：2OAR）到63 x 63 x 1，一起或分别或分别或分别或分别。我们将分析孔径，分子相互作用和压力曲线的变化，这是螺旋倾斜的函数，以探索原子水平上MSCL的可能门控机制。